Faculty Bibliography

Treatment of colorectal cancer beyond surgical resection has had only minimal success in the past. Studies are therefore examining the most advantageous use of currently available treatment methods. Most experience with colorectal cancer has involved 5-fluorouracil; alternatives for adjuvant therapy include combination therapy, immunotherapy, and locoregional therapy. Some success has also been reported with portal vein infusion or intraperitoneal administration of chemotherapeutic agents. Comparison of recurrence data indicates that approximately one third of patients with extrapelvic colorectal cancer can be expected to have peritoneal seeding. Many factors, including selection of patients and chemotherapeutic agents, method of administration, devices used, and techniques for monitoring patients affect the results of any clinical study. Future directions for the adjuvant treatment of colorectal cancer might involve the addition of other agents to the intraperitoneal regimen or of whole abdominal or liver radiation, and also concomitant systemic or portal vein 5-fluorouracil.

Prior to 1974 gastric cancer was considered refractory to chemotherapy. Single agent 5-Fluorouracil, mitomycin, and the nitrosoureas produced modest response rates with no augmentation of survival as compared to historical controls. Combinations of these agents produced slight increases in survival. The addition of doxorubicin, which had no major impact as a single agent, to 5-Fluorouracil and mitomycin C in 1974 produced impressive response rates over 40%, although these early optimistic results were tempered in randomized multi-institutional trials. Nevertheless, median overall survivals appear to have increased with this regimen over historical controls, and the substitution of cisplatin or methyl-CCNU for mitomycin C in Phase II trials has produced equivalent results. Comparison with historical controls is problematic as it is unknown what role more aggressive surgery and supportive measures may have played in increasing survival. Encouraging results with combination therapy in advanced gastric cancer have suggested opportunities to employ combination chemotherapy as adjuvant therapy or together with radiation for locally advanced gastric cancer. The role of less cardiotoxic derivatives of doxorubicin remains to be more fully explored.

In order to test the possible cardiac-sparing effect of doxorubicin administered by six-hour intravenous infusion and to prospectively evaluate the role of resting left ventricular ejection fraction in monitoring these patients, 33 women with advanced breast cancer were treated with combination chemotherapy containing 5-fluorouracil, cyclophosphamide, and doxorubicin. Doxorubicin was administered via a femoral catheter as a six-hour infusion. Cardiac function was monitored prior to therapy and at intervals during therapy by history and physical examination and by measurement of resting left ventricular ejection fraction with gated pool radionuclide angiography. Twenty-six responses were observed (complete response, seven [21 percent]; partial response, 19 [57 percent]). Systemic toxicity included alopecia, myelosuppression, and nausea and vomiting. There was a progressive fall in resting left ventricular ejection fraction during treatment from a median baseline value of 0.63. Mean fall from baseline left ventricular ejection fraction at a cumulative doxorubicin dose of 200 to 300 mg/m2 was 0.06 (p less than 0.005); at 301 to 449 mg/m2 it was 0.09 (p less than 0.0005); and at 450 mg/m2 or greater it was 0.15 (p less than 0.0005). Clinical congestive heart failure developed in three patients. Even though the decrease in left ventricular ejection fraction was often within the 'normal range' (left ventricular ejection fraction 0.50 or greater), these changes were progressive and appeared to be part of a continuum of doxorubicin-induced myocardial damage. Steady-state infusion levels of doxorubicin in plasma ranged from 90 to 120 nM. They confirm the hypothesis that lower concentrations can be achieved by continuous infusion rather than by bolus infusion. In this study, however, administration of doxorubicin by six-hour infusion did not appear to have a major cardiac-sparing effect. Studies of anthracycline cardiac toxicity should include determination of baseline left ventricular ejection fraction and serial observations during therapy. Failure to include deteriorations in function above an arbitrary cutoff point or to make observations only at higher cumulative doses may underestimate drug-induced myocardial damage